Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Ca_v1.2

The L-type Ca²⁺ channel Cav1.2 forms macromolecular signaling complexes that comprise the β₂ adrenergic receptor, trimeric Gs protein, adenylyl cyclase, and cAMP-dependent protein kinase (PKA) for efficient signaling in heart and brain. The protein phosphatases PP2A and PP2B are part of this complex. PP2A counteracts increase in Ca_v1.2 channel activity by PKA and other protein kinases, whereas PP2B can either augment or decrease Ca_v1.2 currents in cardiomyocytes depending on the precise experimental conditions. We found that PP2A binds to two regions in the C-terminus of the central, pore-forming R₁ subunit of Ca _v1.2: one region spans residues 1795-1818 and the other residues 1965-1971. PP2B binds immediately downstream of residue 1971. Injection of a peptide that contained residues 1965-1971 and displaced PP2A but not PP2B from endogenous Cav1.2 increased basal and isoproterenol-stimulated L-type Ca ²⁺ currents in acutely isolated cardiomyocytes. Together with our biochemical data, these physiological results indicate that anchoring of PP2A at this site of Ca_v1.2 in the heart negatively regulates cardiac L-type currents, likely by counterbalancing basal and stimulated phosphorylation that is mediated by PKA and possibly other kinases.